Hypertension (HTN) is a worldwide disease [1]. Population-based studies showed that 972 million adults were hypertensive in 2005 and it is predicted to increase, by about 60% to 1.56 billion by 2025 [2]. Even at early stages, it is a major cause of disability and death for millions of people [3]. Observational studies involving more than 1 million adults from 61 prospective studies have indicated that death from HTN associated cardiovascular diseases (CVDs), both ischemic heart disease and stroke, increases linearly from blood pressure (BP) levels as low as 115/75 mmHg among middle-aged and elderly individuals [4].
BP is a heritable trait with estimates indicating that 30-70% of its variance is attributable to genetic variations [5]. In family studies it varies from ≈31% (single-measure of systolic blood pressure (SBP) and diastolic blood pressure (DBP)), to ≈57% (long-term average of SBP and DBP phenotype) and to ≈68% (24-hour profile of SBP and DBP) [6]. Both BP and HTN are still considered polygenic traits [5]. Inflammation, blood coagulation cascade, cellular adhesion molecules and lipid metabolism all appear to have significant roles [7].
The largest Genome-wide association study (GWAS) on blood pressure including ≈270,000 individuals was recently published [8], reporting 28 loci to be associated with SBP, DBP and/or HTN [8]. Their genetic risk score explained only 0.9% of BP phenotypic variance [8], this representing the so-called ‘dark matter’ of genetic risk [9]. A large ‘hidden heritability’ of unknown nature may be explained by rare variants, structural large variants, epistatic (G*G) and gene*environment interactions [9]. Epistatic interactions may also play an important role in discovering genes that have not yet been found by the consensual single-locus approach [9]. This statement has been extensively reviewed in the last years and both parametric and nonparametric multi-locus methods have been developed to detect such interactions [9]. Epistatic interactions have been documented for susceptibility to cancer [10], morphology [11] and autoimmune conditions [12]. However, to date they have not been extensively studied in HTN and the underlying genetic basis for hypertension remains poorly understood.